X-149487080-T-C

Position:

• chrX-149487080-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000202.8(IDS):​c.1025A>G​(p.His342Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,981 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H342P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: IDS NM_000202.8 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.57

Genes affected

IDS (HGNC:5389): (iduronate 2-sulfatase) This gene encodes a member of the sulfatase family of proteins. The encoded preproprotein is proteolytically processed to generate two polypeptide chains. This enzyme is involved in the lysosomal degradation of heparan sulfate and dermatan sulfate. Mutations in this gene are associated with the X-linked lysosomal storage disease mucopolysaccharidosis type II, also known as Hunter syndrome. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_000202.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-149487080-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 221972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant X-149487080-T-C is Pathogenic according to our data. Variant chrX-149487080-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3255925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDS	NM_000202.8	c.1025A>G	p.His342Arg	missense_variant	8/9	ENST00000340855.11
IDS	NM_001166550.4	c.755A>G	p.His252Arg	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDS	ENST00000340855.11	c.1025A>G	p.His342Arg	missense_variant	8/9	1	NM_000202.8	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097981 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363337

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-II Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 31, 2024	Variant summary: IDS c.1025A>G (p.His342Arg) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183468 control chromosomes. c.1025A>G has been reported in the literature in hemizygous brothers affected with Mucopolysaccharidosis Type II (Hunter Syndrome) (e.g. Lin_2020, Lin_2022). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in reduced IDS enzyme activity in patient leukocytes (50% of WT) or in vitro in COS-7 cells (42% of WT) (e.g. Lin_2020). Multiple different variants located at the same codon (c.1025A>C (p.His342Pro) and c.1024C>T (p.His342Tyr)) have been classified as likely pathogenic/pathogenic in ClinVar (ClinVar ID: 221972, 946154), both citing clinical evidence of variant occurrence in individuals affected with Mucopolysaccharidosis Type II (Hunter Syndrome), supporting a critical relevance of this residue to IDS protein function. The following publications have been ascertained in the context of this evaluation (PMID: 33096603, 35887520). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	literature only	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Jun 07, 2024	Prevalence of the variant significantly increased in affected individuals compared with controls (PS4_Strong), Absent from controls (or at low frequency) in gnomAD database (PM2_Moderate), Missense variant in a gene with a low rate of benign missense variation (PP2_Supporting), Multiple lines of computational evidence support a deleterious effect (PP3_Supporting) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-7.3	D;.
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;.
Vest4		0.94
MutPred		0.79		Gain of ubiquitination at K347 (P = 0.0913);.;
MVP		0.99
MPC		0.87
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.99
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs869025303; hg19: chrX-148568611;